Project Summary/Abstract Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature that leads to right heart failure and death. Patients with scleroderma (SSc) are at high risk for the development of PAH (SSc-PAH), which is a leading cause of death in SSc. While advances in PAH therapeutics have led to improved outcomes, survival in SSc-PAH remains dismal, with 57% of patients dying within 5 years of diagnosis. Thus, there is an urgent need to expand therapeutic options in SSc-PAH, and to identify novel markers of disease risk and severity. PAH pathogenesis is highly complex, with simultaneous dysregulation of multiple biologic pathways, yet current therapies for PAH target just three pathways that regulate vasomotor tone. One potentially targetable metabolic regulator is the protein xanthine oxidoreductase (XOR), which metabolizes purines in an enzymatic reaction that generates uric acid and reactive oxygen species (ROS). Oxidative injury from over-abundant ROS drives endothelial cell dysfunction, altered metabolic signaling, and endothelial apoptosis, all early features of PAH pathobiology. XOR activity increases in experimental PH models, and XOR inhibition with allopurinol prevents pulmonary hypertensive changes from occurring. XOR activity is increased in PAH patients compared to healthy controls, and our preliminary data show that serum UA/XOR levels and purine metabolites significantly correlate with hemodynamics and predict outcomes in SSc-PAH patients. However, XOR has not been studied as a driver of disease and potential therapeutic target in SSc-PAH. We hypothesize that increased XOR activity contributes to PAH development in SSc and drives disease progression through oxidative injury and altered metabolism. By leveraging two rich data sources ? the world's largest known SSc serum biorepository, and an NIH-sponsored prospective cohort of newly diagnosed SSc-PAH patients - we aim to 1) demonstrate that increased XOR activity and oxidative stress influence development of PAH in patients with scleroderma, 2) link XOR activity and oxidative stress with phenotypic and outcome data in SSc-PAH (with a special focus on right ventricular structural and functional phenotypes), and 3) identify metabolic patterns associated with poor clinical response to currently available PAH therapies. These aims will examine the role of XOR activity and oxidative stress in SSc-PAH in order to clarify the potential of XOR as a therapeutic target, and to lay a groundwork for personalized selection of PAH therapies in SSc.